Tyrosine Kinase Signaling in Cancer Metabolism: PKM2 Paradox in the Warburg Effect

The Warburg Effect, or aerobic glycolysis, is one of the major metabolic alterations observed in cancer. Hypothesized to increase a cell's proliferative capacity via regenerating NAD+, increasing the pool of glycolytic biosynthetic intermediates, and increasing lactate production that affects the tumor microenvironment, the Warburg Effect is important for the growth and proliferation of tumor cells. The mechanisms by which a cell acquires the Warburg Effect phenotype are regulated by the expression of numerous oncogenes, including oncogenic tyrosine kinases. Oncogenic tyrosine kinases play a significant role in phosphorylating and regulating the activity of numerous metabolic enzymes. Tyrosine phosphorylation of glycolytic enzymes increases the activities of a majority of glycolytic enzymes, thus promoting increased glycolytic rate and tumor cell proliferation. Paradoxically however, tyrosine phosphorylation of pyruvate kinase M2 isoform (PKM2) results in decreased PKM2 activity, and this decrease in PKM2 activity promotes the Warburg Effect. Furthermore, recent studies have shown that PKM2 is also able to act as a protein kinase using phosphoenolpyruvate (PEP) as a substrate to promote tumorigenesis. Therefore, numerous recent studies have investigated both the role of the classical and non-canonical activity of PKM2 in promoting the Warburg Effect and tumor growth, which raise further interesting questions. In this review, we will summarize these recent advances revealing the importance of tyrosine kinases in the regulation of the Warburg Effect as well as the role of PKM2 in the promotion of tumor growth.

• Publication year

  2018

• Venue

  Front. Cell Dev. Biol.

• Publication date

  2018-07-24

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.3389/fcell.2018.00079PMID 30087897PMCID 6066570
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The Science and Translation of Lactate Shuttle Theory.

  2018influential reference
• Curcumin decreases Warburg effect in cancer cells by down-regulating pyruvate kinase M2 via mTOR-HIF1α inhibition

  2018cited by this paper
• Posttranslational Modifications of Pyruvate Kinase M2: Tweaks that Benefit Cancer

  2018cited by this paper
• PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth.

  2018influential reference
• Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma

  2018influential reference
• Lactate Metabolism in Human Lung Tumors.

  2017influential reference
• Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation.

  2017cited by this paper
• PKM2 is not required for colon cancer initiated by APC loss

  2017cited by this paper
• Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate

  2017cited by this paper
• Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.

  2016cited by this paper
• Evidence That Does Not Support Pyruvate Kinase M2 (PKM2)-catalyzed Reaction as a Rate-limiting Step in Cancer Cell Glycolysis*

  2016cited by this paper
• AKT-induced PKM2 phosphorylation signals for IGF-1-stimulated cancer cell growth

  2016cited by this paper
• PKM2, cancer metabolism, and the road ahead

  2016cited by this paper
• Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

  2016cited by this paper
• PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis

  2016influential reference
• Lactate Metabolism is Associated with Mammalian Mitochondria

  2016influential reference
• PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation

  2015cited by this paper
• Melanoma brain metastasis is independent of lactate dehydrogenase A expression.

  2015cited by this paper
• Inhibition of LDHA suppresses tumor progression in prostate cancer

  2015cited by this paper
• Lack of Evidence for PKM2 Protein Kinase Activity.

  2015cited by this paper
• Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation.

  2014cited by this paper
• Tyr-301 Phosphorylation Inhibits Pyruvate Dehydrogenase by Blocking Substrate Binding and Promotes the Warburg Effect*

  2014cited by this paper
• PKM2 phosphorylates MLC2 and regulates cytokinesis of tumor cells

  2014cited by this paper
• Tyr-94 Phosphorylation Inhibits Pyruvate Dehydrogenase Phosphatase 1 and Promotes Tumor Growth*

  2014cited by this paper
• Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis.

  2014cited by this paper
• PKM2 regulates chromosome segregation and mitosis progression of tumor cells.

  2014cited by this paper
• PKM2 inhibitor shikonin suppresses TPA‐induced mitochondrial malfunction and proliferation of skin epidermal JB6 cells

  2014cited by this paper
• Post-translational modifications and the Warburg effect

  2013cited by this paper
• Proviral Insertion in Murine Lymphomas 2 (PIM2) Oncogene Phosphorylates Pyruvate Kinase M2 (PKM2) and Promotes Glycolysis in Cancer Cells*

  2013cited by this paper
• PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells.

  2013influential reference
• Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation

  2013cited by this paper
• JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism

  2013cited by this paper
• Protein Tyrosine Phosphatase 1B Regulates Pyruvate Kinase M2 Tyrosine Phosphorylation*

  2013cited by this paper
• Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase.

  2012cited by this paper
• Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

  2012cited by this paper
• Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth.

  2012cited by this paper
• Mouse Genetics Suggests Cell-Context Dependency for Myc-Regulated Metabolic Enzymes during Tumorigenesis

  2012cited by this paper
• M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth

  2012cited by this paper
• PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis.

  2012cited by this paper
• Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons.

  2012cited by this paper
• ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect

  2012cited by this paper
• Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.

  2011cited by this paper
• Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism.

  2011cited by this paper
• Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.

  2011cited by this paper
• Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses

  2011influential reference
• Hallmarks of cancer: the next generation.

  2011cited by this paper
• Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation

  2011cited by this paper
• Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth.

  2011influential reference
• Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2

  2011cited by this paper
• Tyrosine Phosphorylation of Lactate Dehydrogenase A Is Important for NADH/NAD+ Redox Homeostasis in Cancer Cells

  2011influential reference
• HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer

  2010cited by this paper
• Open Access RESEARCH

  2010cited by this paper
• Evidence for an Alternative Glycolytic Pathway in Rapidly Proliferating Cells

  2010cited by this paper
• Identification of small molecule inhibitors of pyruvate kinase M2.

  2010cited by this paper
• Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth

  2009influential reference
• Pyruvate kinase M2 is a phosphotyrosine-binding protein

  2008cited by this paper
• The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

  2008cited by this paper
• Cooperating gene mutations in acute myeloid leukemia: a review of the literature

  2008cited by this paper
• Inhibitory effect of tumor cell-derived lactic acid on human T cells.

  2007cited by this paper
• Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.

  2006cited by this paper
• Tumor-derived lactic acid modulates dendritic cell activation and antigen expression.

  2006cited by this paper
• Targeting Tyrosine Kinases in Cancer: The Second Wave

  2006cited by this paper
• Why do cancers have high aerobic glycolysis?

  2004cited by this paper
• Evaluation of Myc E-Box Phylogenetic Footprints in Glycolytic Genes by Chromatin Immunoprecipitation Assays

  2004cited by this paper
• Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes.

  2004cited by this paper
• FLT3: ITDoes matter in leukemia

  2003cited by this paper
• MRI of the tumor microenvironment

  2002cited by this paper
• Oncogenic kinase signalling

  2001influential reference
• The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate.

  1998influential reference
• c-Myc transactivation of LDH-A: implications for tumor metabolism and growth.

  1997cited by this paper
• Regulation of M2-type pyruvate kinase from human meningioma by allosteric effectors fructose 1,6 diphosphate and L-alanine.

  1992cited by this paper
• Glycolysis—one of the keys to cancer?

  1980influential reference
• Influence of salt, substrate, and cofactor concentrations on the kinetic and mechanistic behavior of phosphoglycerate mutase.

  1968influential reference
• On the origin of cancer cells.

  1956cited by this paper
• [Origin of cancer cells].

  1956cited by this paper

• Curcumol targets the ATG4B-PKM2-lactate signaling axis to reverse EMT and inhibit colorectal cancer liver metastasis.

  2026cites this paper
• Sugars to signals: emerging roles of PAK1 in re-wiring glucose metabolism in cancers

  2025cites this paper
• PTPRJ-Targeting Peptide Agonist Induces Broad Cellular Signaling Perturbations and DNA Damage in Lung Cancer Cells

  2025cites this paper
• A review on the role of pyruvate kinase M2 in cancer: From metabolic switch to transcriptional regulation.

  2025cites this paper
• Macrophage plasticity and glucose metabolism: the role of immunometabolism in pulmonary arterial hypertension

  2025cites this paper
• Pyruvate kinase M2 plays pivotal role on promoting PD-L1 expression and malignant behaviors of hepatoma cells

  2025cites this paper
• Molecular mechanisms of glucose metabolism disorders in tumors of the female reproductive system

  2025cites this paper
• Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status

  2025cites this paper
• The novelty of profilin 2 in regulating pyruvate kinase M2 nuclear translocation and promoting tumor angiogenesis in lung adenocarcinoma

  2025cites this paper
• PKM2 functions as a histidine kinase to phosphorylate PGAM1 and increase glycolysis shunts in cancer

  2024cites this paper
• Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.

  2024cites this paper
• Mapping the expression and functional landscape of key enzymes in glucose metabolism within human gynecological tumors.

  2024cites this paper
• Hyaluronic Acid Influences Amino Acid Metabolism via Differential L-Type Amino Acid Transporter 1 Expression in the U87-Malignant Glioma Cell Line.

  2024cites this paper
• Overexpression of TSPAN8 in consensus molecular subtype 3 colorectal cancer.

  2024cites this paper
• Parallel phosphoproteomics and metabolomics map the global metabolic tyrosine phosphoproteome

  2024cites this paper
• Tyrosine phosphatase SHP2 aggravates tumor progression and glycolysis by dephosphorylating PKM2 in gastric cancer

  2024cites this paper
• Thanksgiving to Yeast, the HMGB Proteins History from Yeast to Cancer

  2023cites this paper
• The ratio of PKM1/PKM2 is the key factor affecting the glucose metabolism and biological function of colorectal cancer cells

  2023cites this paper
• Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma

  2023cites this paper
• RETRACTED ARTICLE: Dihydroartemisinin enhances the anti-tumour effect of photodynamic therapy by targeting PKM2-mediated glycolysis in oesophageal cancer cell

  2023cites this paper
• Mitochondrial Dynamics in Ovarian Cancer: Pathophysiology and Therapeutic Implications

  2023cites this paper
• Cryopreservation Induces Acetylation of Metabolism-Related Proteins in Boar Sperm

  2023cites this paper
• Shikonin inhibits immune checkpoint PD-L1 expression on macrophage in sepsis by modulating PKM2.

  2023cites this paper
• The “sweet” path to cancer: focus on cellular glucose metabolism

  2023cites this paper
• Reduction in gefitinib resistance mediated by Yi-Fei San-Jie pill in non-small cell lung cancer through regulation of tyrosine metabolism, cell cycle, and the MET/EGFR signaling pathway.

  2023cites this paper
• Proteomic Profiling of Mouse Brain Pyruvate Kinase Binding Proteins: A Hint for Moonlighting Functions of PKM1?

  2023cites this paper
• Expression of substance P, neurokinin 1 receptor, Ki-67 and pyruvate kinase M2 in hormone receptor negative breast cancer and evaluation of impact on overall survival

  2023cites this paper
• Transcriptomic signatures responding to PKM2 activator TEPP-46 in the hyperglycemic human renal proximal epithelial tubular cells

  2022cites this paper
• CRNDE silencing promotes apoptosis and enhances cisplatin sensitivity of colorectal carcinoma cells by inhibiting the Akt/mTORC1-mediated Warburg effect

  2022cites this paper
• Inhibition of PKM2 Enhances Sensitivity of Olaparib to Ovarian Cancer Cells and Induces DNA Damage

  2022cites this paper
• Circulating Long Non-Coding RNAs LINC00324 and LOC100507053 as Potential Liquid Biopsy Markers for Esophageal Squamous Cell Carcinoma: A Pilot Study

  2022cites this paper
• LncCCAT1 interaction protein PKM2 upregulates SREBP2 phosphorylation to promote osteosarcoma tumorigenesis by enhancing the Warburg effect and lipogenesis

  2022cites this paper
• Potential of PKM2 as a drug target in mouse models with type 1 diabetes mellitus

  2022cites this paper
• Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy

  2022cites this paper
• The Role of PKM2 in the Regulation of Mitochondrial Function: Focus on Mitochondrial Metabolism, Oxidative Stress, Dynamic, and Apoptosis. PKM2 in Mitochondrial Function

  2022cites this paper
• The C-Terminal Acidic Tail Modulates the Anticancer Properties of HMGB1

  2022cites this paper
• Single-Cell FISH Analysis Reveals Distinct Shifts in PKM Isoform Populations during Drug Resistance Acquisition

  2022cites this paper
• miR-140-3p/usp36 axis mediates ubiquitination to regulate PKM2 and suppressed the malignant biological behavior of breast cancer through Warburg effect

  2022influential citation
• Pharmacological activation of pyruvate kinase M2 reprograms glycolysis leading to TXNIP depletion and AMPK activation in breast cancer cells

  2021cites this paper
• MiR-21-5p inhibition attenuates Warburg effect and stemness maintenance in osteosarcoma cells via inactivation of Wnt/β-catenin signaling.

  2021cites this paper
• The role of B7-H3 in tumors and its potential in clinical application.

  2021cites this paper
• The Intersection of Purine and Mitochondrial Metabolism in Cancer

  2021cites this paper
• Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents.

  2021cites this paper
• Vitamin D affects the Warburg effect and stemness maintenance of non-small-cell lung cancer cells by regulating PI3K/AKT/mTOR signaling pathway.

  2021cites this paper
• Hyperbaric Oxygen Therapy Represses the Warburg Effect and Epithelial–Mesenchymal Transition in Hypoxic NSCLC Cells via the HIF-1α/PFKP Axis

  2021cites this paper
• Enzymatic Activation of Pyruvate Kinase Increases Cytosolic Oxaloacetate to Inhibit the Warburg Effect

  2021cites this paper
• Circ-BANP Contributes to Cell Carcinogenesis and Aerobic Glycolysis by Regulating MAPK1 Through miR-874-3p in Colorectal Cancer

  2021cites this paper
• PKM2 regulates proliferation and apoptosis through the Hippo pathway in oral tongue squamous cell carcinoma

  2021cites this paper
• Pyruvate kinase M2 in chronic inflammations: a potpourri of crucial protein–protein interactions

  2021cites this paper
• The Hallmarks of Flavonoids in Cancer

  2021cites this paper
• Isovitexin potentiated the antitumor activity of cisplatin by inhibiting the glucose metabolism of lung cancer cells and reduced cisplatin-induced immunotoxicity in mice.

  2021cites this paper
• A short review on cross-link between pyruvate kinase (PKM2) and Glioblastoma Multiforme

  2021cites this paper
• Extracellular vesicles induce aggressive phenotype of luminal breast cancer cells by PKM2 phosphorylation

  2021cites this paper
• PKM2 promotes cell metastasis and inhibits autophagy via the JAK/STAT3 pathway in hepatocellular carcinoma

  2021cites this paper
• The expression and role of glycolysis-associated molecules in infantile hemangioma.

  2020cites this paper
• Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis

  2020cites this paper
• Interrogation of kinase genetic interactions provides a global view of PAK1-mediated signal transduction pathways

  2020cites this paper
• Flavonoids against the Warburg phenotype—concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism

  2020cites this paper
• Metabolic Plasticity of Melanoma Cells and Their Crosstalk With Tumor Microenvironment

  2020cites this paper
• Quantitative acetylome and phosphorylome analysis reveals Girdin affects pancreatic cancer progression through regulating Cortactin

  2020cites this paper
• Aerobic Glycolysis in the Retina: Functional Roles of Pyruvate Kinase Isoforms

  2020cites this paper
• Cell-Type Specific Metabolic Response of Cancer Cells to Curcumin

  2020cites this paper
• Benzene and its effects on cell signaling pathways related to hematopoiesis and leukemia

  2020cites this paper
• Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract

  2020cites this paper
• Significance of alternative splicing in cancer cells

  2019cites this paper
• Serotonin activates glycolysis and mitochondria biogenesis in human breast cancer cells through activation of the Jak1/STAT3/ERK1/2 and adenylate cyclase/PKA, respectively

  2019cites this paper
• Can Metabolic Pathways Be Therapeutic Targets in Rheumatoid Arthritis?

  2019cites this paper
• Pyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment

  2019cites this paper
• PKM2, function and expression and regulation

  2019cites this paper
• Regulation of mitotic spindle orientation by phosphorylation of end binding protein 1.

  2019cites this paper
• Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2)

  2019cites this paper
• PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma

  2019cites this paper
• High Expression of Glycolytic Genes in Cirrhosis Correlates With the Risk of Developing Liver Cancer

  2018cites this paper
• The Multiple Roles of Peptidyl Prolyl Isomerases in Brain Cancer

  2018cites this paper
• The ERK and JNK pathways in the regulation of metabolic reprogramming

  2018cites this paper
• Methylation Controlled J Protein Is A Master Regulator Of Mitochondrial Metabolism

  2018cites this paper